Role of CDCP1 in the pathogenesis of autoimmune uveitis

CDCP1在自身免疫性葡萄膜炎发病机制中的作用

• 批准号: 10655755
• 负责人: FENG C LIN
• 金额: $ 50.4万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655755
• 关键词: Activated-Leukocyte Cell Adhesion Molecule; Active Immunization; Adoptive Transfer; Arrestins; Attenuated; Autoimmune Diseases; Biological Assay; Blindness; Blocking Antibodies; Blood-Retinal Barrier; CD6 antigen; Cell surface; Cytoskeleton; Data; Development; Disease; Endothelium; Epithelium; Event; Extracellular Domain; Flow Cytometry; Genetic; Human; Impairment; In Vitro; Infiltration; Interleukin-6; Knock-out; Knockout Mice; Knowledge; Ligands; Mediating; Monoclonal Antibodies; Mus; Myosin ATPase; Pathogenicity; Pathologic; Penetration; Permeability; Phosphorylation; Pre-Clinical Model; Process; Production; Proteins; Proteomics; Reagent; Reporting; Research; Retina; Role; Signal Transduction; Stress Fibers; Structure of retinal pigment epithelium; Surface; Surface Plasmon Resonance; T cell infiltration; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; TFRC gene; Testing; Therapeutic Uses; Therapeutic antibodies; Tight Junctions; Treatment Efficacy; Uveitis; Work; autoimmune pathogenesis; autoimmune uveitis; cell motility; conditional knockout; cytokine; efficacy evaluation; extracellular; immunogenicity; immunoregulation; in vivo; inhibiting antibody; insight; knock-down; migration; mutant; nanobodies; new therapeutic target; next generation; novel; novel therapeutic intervention; protein protein interaction; receptor; selective expression; targeted treatment; therapeutic target

ABSTRACT Autoimmune uveitis is a major cause of blindness for which no cure and limited treatment options are available. We found that CUB domain-containing protein 1 (CDCP1) knockout (KO) mice are protected from experimental autoimmune uveitis (EAU) induced by adoptive transfer of pre-activated uveitogenic T cells, suggesting that CDCP1 facilitates pathogenic T cell infiltration through the blood–retina barrier (BRB) to induce EAU. In pilot mechanistic studies, we discovered that CDCP1 is selectively expressed on retinal pigmented epithelial cells (RPEs) in the retina and identified CD71, an established T cell activation marker, as a new ligand of CDCP1 in addition to CD6, another T cell marker. Stimulation with CD6 or CD71 induced CDCP1-mediated RPE cytoskeletal remodeling, a process known to impair epithelial barrier functions, and increased RPE production of IL-6, a pathogenic cytokine known to disrupt the endothelial barrier integrity. These intriguing data provide strong evidence in support of CDCP1 as a novel immunoregulator that interacts with CD6 and CD71 on T cells to facilitate pathogenic T cell infiltration through the BRB to induce EAU. Further, our data suggest that CDCP1 could be targeted for treating autoimmune uveitis. In this proposed study, we aim to use the unique reagents that we have developed or obtained in our preliminary studies to elucidate the detailed mechanisms by which CDCP1 regulates both the outer and inner BRB to facilitate T cell infiltration into the retina, and to determine the potential of CDCP1-targeted therapeutics using various conditional KO mice and our already developed anti-CDCP1 monoclonal antibodies and nanobodies. The proposed work should provide novel insights into our understanding of the pathogenesis of autoimmune uveitis and open new avenues of research in which CDCP1 is explored as a key immunoregulator and new therapeutic target for this blinding disease.

摘要 自身免疫性葡萄膜炎是失明的主要原因，目前尚无治愈方法，治疗选择有限。 available.我们发现，CUB结构域蛋白1（CDCP 1）基因敲除（KO）小鼠可以免受 通过过继转移预活化的葡萄膜原性T细胞诱导的实验性自身免疫性葡萄膜炎（EAU）， 这表明CDCP 1促进致病性T细胞通过血-视网膜屏障（BRB）浸润，以诱导 EAU。在初步机制研究中，我们发现CDCP 1选择性地表达于视网膜色素上皮细胞， 视网膜上皮细胞（RPE），并确定CD 71，一个既定的T细胞活化标志物，作为一种新的配体， CDCP 1和另一种T细胞标志物CD 6。用CD 6或CD 71刺激诱导CDCP 1介导的 RPE细胞骨架重塑，一个已知损害上皮屏障功能的过程， IL-6的产生，IL-6是已知破坏内皮屏障完整性的致病性细胞因子。这些有趣的数据 提供了强有力的证据支持CDCP 1作为一种新型免疫调节剂，与CD 6和CD 71相互作用， T细胞以促进病原性T细胞通过BRB浸润以诱导EAU。此外，我们的数据表明， CDCP 1可作为治疗自身免疫性葡萄膜炎的靶点。在这项研究中，我们的目标是使用独特的 我们已经开发或在我们的初步研究中获得的试剂，以阐明详细的机制， CDCP 1调节外BRB和内BRB以促进T细胞浸润到视网膜中， 使用各种条件性KO小鼠确定CDCP 1靶向治疗的潜力， 开发了抗CDCP 1单克隆抗体和纳米抗体。拟议的工作应提供新颖的 深入了解自身免疫性葡萄膜炎的发病机制，并开辟新的研究途径 其中CDCP 1被探索为这种致盲性疾病的关键免疫调节剂和新的治疗靶点。